Process for preparing thiazole derivative and the intermediate compounds for preparing the same

ABSTRACT

The present invention provides a process for preparing thiazole derivatives of formula (XI), that activate the delta subtype of the human Peroxisome Proliferator Activated Receptor (hPPARδ), and also provides processes for compounds of formula (VI), (VII), (VIII) and (IX), intermediate compounds for preparation of the above compounds of formula (XI).

TECHNICAL FIELD

The present invention relates to a process for preparing thiazolederivative of formula (XI), that activates the delta subtype of thehuman Proxisome Proliferator Activated Receptor (hPPARδ), and alsorelates to the compounds of formula (VI), (VII), (VIII) and (IX),intermediate compounds for preparation of the above compound of formula(XI).

BACKGROUND ART

Especially,2-{2-methyl-4-[({4-metyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-yl}methyl)sulfonyl]phenoxy}aceticacid (hereinafter, called to “GW501516”) among thiazole derivatives offormula (XI) showed an excellent effect to treatment of obesity inanimal models (Cell 2003, 113, 159), and proved effectiveness incardiovascular disease by increasing high density lipoprotein (HDL) anddecreasing low density lipoprotein (LDL) effectively in the animalexperiment (Proc. Natl. Acad. USA 2001, 98, 5306) and in clinical trial.And the process for preparation of the said substance has been disclosedin PCT publication WO 01/00603A1 and Bioorg. Med Chem. Lett. 2003, 13,1517, in which GW501516 (13) was prepared, as shown in the followingscheme(1). Methyl (4-mercapto-3-methylphenoxy)acetate (7), synthesizedfrom the starting material, 4′-hydroxy-3′-methylacetophenone (1), via 6steps, was coupled to5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)thiazole (11), whichwas prepared from 4-(trifluoromethyl)thiobenzamide (8) via 3 steps, inthe presence of excessive cesium carbonate to obtain the methyl ester(12) of GW501516, and then treating the ester with 1 N lithium hydroxideto give GW501516.

As an alternative synthesis method of GW501516, it is disclosed asillustrated in the following scheme (2), that the compound (13) ofGW501516 can be prepared by introducing ethyl acetate group to o-cresol(14), reacting the resulted coruppund (15) with sulfonyl chloride,reducing the resulted compound (16) with tin (Sn) under acidic conditionto form ethyl (4-mercapto-2-methyl phenoxy)acetate (17), reacting itwith 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11)together with an excessive cesium carbonate to obtain the ethyl esterintermediate (18) of GW501516, and deprotecting the ester group of theintermediate compound with 1 N lithium hydroxide.

Although the above compound (13) has known to be an excellent efficacyin the treatment of obesity in animal models and in the treatment ofdisease states associated with cholesterol metabolism in clinicaltrials, the manufacturing method thereof was not satisfactory, therebybeing not cost-effective. That is to say,

1) The manufacturing method of reaction scheme (I) consists of 12 steps,and the total yield thereof is as low as 2%. So, it is not proper to beapplied to the industry, due to its extreme low production yield.

2) The manufacturing process according to the reaction scheme (1)includes three refluxing steps at elevated temperature for 16 hours,which takes long time to obtain the final product.

3) Tin (Sn) powder used in reaction scheme (2) is very unstable to themoisture, and moreover, it is a combustible metal, thereby being verydangerous to adopt it in industrial scale.

4) An excessive tin (Sn) powder used in the reaction scheme (2) may leadto pollution of the environment.

5) A separated another step for reacting compound (11) with compound (7)or compound (17) in the reaction scheme (1) or (2) is required, and alsoan excess amount of cesium carbonate, which is not common inorganicbase, is used, and also the reaction time is comparatively long.

6) The hydrolysis steps of methyl or ethyl ester using 1 N lithiumhydroxide in reaction scheme (1) or (2) requires a long reaction time,about 16 hours, of which yield is as low as 60%.

7) Methyl or ethyl (4-mercapto-2-methylphenoxy)acetate (7) or (17)obtained as an intermediate compound in the reaction scheme (1) or (2)is unstable, so the respective compound can be easily changed todisulfides, which results in lowering the total reaction yield.

Under the circumstance, the novel process for preparing the abovecompound with easiness and low cost has been demanded in the art.

DISCLOSURE OF THE INVENTION

In view of the above situation, the inventors of the present inventionhave conducted extensive studies on the novel processes for preparingcompounds of the following formula (XI). As a result, the inventors havefound that the said compounds can be easily prepared as shown in thefollowing reaction scheme. That is to say, 4-halogenated phenols offormula (V) are converted into compounds of formula (VI) which arestable to the base, the halogen group of compound (VI) is substitutedwith metal such as lithium or magnesium, and then they are convertedinto the metal thiolate intermediate compounds of formula (VII), usingsulfur. The compounds (VII) are reacted with compounds of formula (IV)without separation and purification step, which are prepared fromcompounds of formula (I) via several steps, to obtain thioethercompounds of formula (VIII) easily. It is subjected to deprotecting thephenol residue to get compounds of formula (IX), which are reacted withalkyl halogenated acetate to give compounds of formula (X), and thenthey are hydrolyzed to have compounds of formula (XI).

wherein

-   -   R₁ represents hydrogen atom, CF₃, or halogen atom,    -   n is an integer of 0 to 5,    -   R₂ represents a hydrogen atom, fluorine atom, chlorine atom,        —(C₁-C₄) alkyl, —O(C₁-C₄) alkyl, —S(C₁-C₄) alkyl, or        —N(C₁-C₄alkyl)₂ group,    -   R₃ represents a protecting group having a tetrahydropyranyl.        —(C₁-C₄) alkyl, allyl, or silyl group such as alkylsilyl,        alkylarylsilyl,    -   R₄ represents a —(C₁-C₄) alkyl group,    -   X₁ represents a halogen atom,    -   X₂ represents a halogen atom, or leaving group easily displaced        by nucleophiles, and    -   M represents a lithium ion or magnesium halide (Cl, Br, or I).

An object of the present invention is to provide a process for preparingcompounds of formula (XI) in high yield in a short period, via unstableintermediate compounds without separation step in the reaction.

The present invention also provides a process for preparing compounds offormula (II), which comprises by reacting compounds of formula (I) withalkyl 2-chloroacetoacetate.

The present invention further provides a process for preparing compoundsof formula (III), which comprises by reducing the ester group ofcompounds of formula (II).

The present invention further provides a process for preparing compoundsof formula (IV), which comprises by introducing a leaving group tocompounds of formula (III).

The present invention further provides a process for preparing compoundsof formula (VI), which comprises by reacting compounds of formula (V)with a phenol protecting group.

The present invention further provides a process for preparing compoundsof formula (VIII), which comprises by reacting compounds of formula (VI)with metallic or organometallic reagents and sulfur to form compounds offormula (VII), and reacting them with compounds of formula (IV) withouta specific organic or inorganic base.

The present invention further provides a process for preparing compoundsof formula (IX), which comprises by eliminating the protecting group ofphenol of compounds of formula (VIII).

The present invention further provides a process for preparing compoundsof formula (X), which comprises by reacting compounds of formula (IX)with alkyl haloacetate in the presence of organic or inorganic base.

The present invention further provides a process for preparing compoundsof formula (XI), which comprises by subjecting the ester compounds offormula (X) to hydrolyze.

The present invention further provides processes for the novel compoundsof formula (VI), (VII), (VIII), and (IX), each of which useful asintermediate compounds for preparation of the final products of thepresent invention.

BEST MODE FOR CARRYING OUT THE INVENTION

In a process for preparation of compounds of formula (XI) according tothe present invention, R₁ represents hydrogen atom, CF₃, or halogenatom, and the number (n) of the substituent is 0 to 5 of the same ordifferent one.

R₂ stands for hydrogen atom, fluorine atom, chlorine atom, —O-alkyl,—S-alkyl, or —N-(alkyl)₂ (alkyl group having 1 to 4 carbon atoms). Theposition of each substituent is ortho- or meta- to the phenol group, andthe number of substituent is 1 or 2.

R₃ is a protecting group, and includes a tetrahydropyranyl, alkyl orallyl group having 1 to 4 carbon atoms, or silyl group such astrimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.Preferred examples of the protecting groups among them includetert-butyl, tetrahydropyranyl and silylated groups.

R₄ is a protecting group, and examples thereof include alkyl having 1 to4 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, andtert-butyl group. Of these, methyl, ethyl, and propyl are preferred.

Example of the halogen atom represented by X₁ includes a fluorine atom,chlorine atom, bromine atom or iodine atom.

X₂ represents a leaving group, which can be easily displaced by metalthiolate in nucleophilic substitution reaction.

Examples thereof include a halogen atom, methanesulfonate (MsO—), andp-tolunesulfonate (TsO—). Here, the halogen atom means a fluorine atom,chlorine atom, bromine atom or iodine atom.

M represents a lithium ion or magnesium halide (Cl, Br, or I).

The compounds of the formula (I) and (V) are commercially available orcan be synthesized easily by using known methods in the art.

The process of the present invention will be described as set below.

[Step A] Preparation of Compounds of Formula (II):

Compounds of formula (II) can be prepared by reacting compounds offormula (I) with ethyl or methyl 2-chloroacetoacetate in a solvent.

Suitable solvents usable in this reaction include alcohols such asmethanol, ethanol, propanol, and butanol; and ethers such as diethylether, tetrahydrofuran, and 1,4-dioxane. Of these, ethanol ortetrahydrofuran is preferred as a solvent.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct the reaction at 25 to 150° C. for 6hours to 1 day, more preferably 60 to 120° C. within 16 hours.

[Step B] Preparation of Compounds of Formula (III):

Compounds of formula (III) can be prepared by reducing the ester moietyof compounds of formula (II) in an anhydrous solvent.

As reducing agents, aluminum hydrides such as lithium aluminum hydride,and diisobutylaluminum hydride, and boron hydrides such as sodiumborohydride and lithium borohydride can be given. Among them, lithiumaluminum hydride and diisobutylaluminum hydride are preferred.

As anhydrous solvents usable in this reaction, diethyl ether,tetrahydrofuran, and dichloromethane can be given, with preferably,dichloromethane.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct the reaction at −100 to 60° C. for30 minutes to 6 hours, more preferably −78 to 25° C. within 2 hours.

[Step C] Preparation of Compounds of Formula (IV):

Compounds of formula (IV) can be prepared by subjecting halogenationreaction on compounds of formula (III), or reacting compounds of formula(III) with methanesulfonyl chloride or p-toluene sulfonyl chloride in asolvent.

Suitable solvents usable in this include N,N-dimethylformamide, diethylether, tetrahydrofuran, tetrachloromethane, chloroform, dichloromethane,and pyridine. Of these, dichloromethane for halogenation reaction, andpyridine for methanesulfonate or p-toluenesulfonate reactionrespectively are preferred.

Suitable reagents for halogenation reaction to the alcohol moietyinclude triphenylphosphine (TPP) with N-chlorosuccinimide (NCS),triphenylphosphine with chlorine gas, triphenylphosphine withtetrachloromethane(CCl₄), phosphorus pentachloride (PCl₅),thionylchloride (SOCl₂), and methanesulfonyl chloride (MeSO₂Cl) forintroduction of chlorine atom; triphenylphosphine withN-bromosuccinimide (NBS), triphenylphosphine with bromine gas,triphenylphosphine with tetrabromomethane (CBr₄), phosphoruspentabromide (PBr₅), and thionyl bromide (SOBr₂) for introduction ofbromine atom; triphenylphosphine with N-iodosuccine imide,triphenylphosphine with solid iodine, and triphenylphosphine withtetraiodomethane (Cl₄) for introduction of iodine atom. Alternatively,introduction of iodine atom can be carried out by substituting chloro-or bromocompounds of formula (IV) with sodium iodide(NaI) in acetone,so-called halogen-iodine substitution method. Of these, the preferredleaving group is chlorine or bromine atom, and the preferred reagent forthis reaction is triphenylphosphine with N-chlorosuccinimide orN-bromosuccinimide.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −10 to 40° C. for30 minutes to 1 day, more preferably 10 to 25° C. within 2 hours.

[Step D] Preparation of Compounds of Formula (VI):

Compounds of formula (VI) can be prepared by reacting compounds offormula (V) with conventional compounds for protecting phenol group inthe presence of a base in a solvent.

Suitable solvents usable in this reaction include N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethylacetate, tetrachloromethane, chloroform, and dichloromethane as aproticpolar solvents; tetrahydrofuran, 1,4-dioxane, dimethoxy ethane, anddiethylene glycol dimethyl ether as ethers; and benzene, toluene, andxylene as aromatic hydrocarbons. Of these, an aprotic polar solvent ispreferred, with N,N-dimethylformamide, chloroform, or dichloromethanebeing particularly preferred.

Suitable base usable for reacting silyl protecting group with phenolinclude amines such as pyridine, triethylamine, imidazole, andN,N-dimethylaminopyridine.

Suitable bases usable for reacting aryl ether protecting group withphenol include sodium hydroxide, potassium hydroxide, sodium carbonate,and potassium carbonate. As the preferred bases among the above,imidazole and potassium carbonate can be given.

Tetrahydropyranyl (THP) protection on the phenol group can be achievedby reacting 3,4-dihydro-2H-pyran with alkyl or aryl triphenylphosphoniumbromide.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −10 to 80° C. for 1hour to 1 day, more preferably 0 to 25° C. within 4 hours.

[Step E] Preparation of Compounds of Formula (VIII):

Compounds of formula (VIII) can be prepared by reacting intermediatecompounds of formula (VII), without separation, with compounds offormula (IV) in an anhydrous solvent.

Suitable anhydrous solvents usable in this reaction include diethylether, tetrahydrofuran, hexane, and heptane. These solvents may be usedeither singly or in combination of two. Diethyl ether, tetrahydrofuran,and a mixed solvent of diethyl ether with tetrahydrofuran areparticularly preferred.

As suitable metallic reagents used for halogen-metal substitution,lithium metal and magnesium metal can be given, and as organometallicreagents, n-butyllithiurn, sec-butyllithium, and tert-butyllithium canbe used. Of these, organometallic reagents are preferred, withn-butyllithium and tert-butyllithium being particularly preferred.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −100 to 25° C. for30 minutes to 1 day, more preferably in the step of sulfur introductionat −78° C., later raising the reaction temperature up to 25° C. for 1hour after introduction of compounds of formula (IV) into the reactionmixture.

[Step F] Preparation of Compounds of Formula (IX):

Compounds of formula (IX) can be prepared by eliminating thephenol-protecting group of compounds of formula (VIII) in a solvent.

Suitable solvents usable in this reaction include N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethylacetate, tetrachloromethane, chloroform, and dichloromethane as polarsolvents; tetrahydrofuran, 1,4-dioxane, dimethoxy ethane, and diethyleneglycol dimethyl ether as ethers; and benzene, toluene, and xylene asaromatic hydrocarbons. Of these, tetrahydrofuran is particularlypreferred.

Suitable reagents for elimination of the protecting groups of methyl,ethyl, tert-butyl, benzyl, allyl on the phenol group include a Lewisacid such as trimethylsilyliodide, ethane thioalcohol, lithium iodide,aluminum bromide, aluminum chloride, boron triiodide, andtrifluoroacetic acid; suitable reagents for elimination of silylatedprotecting groups such as trimethylsilyl, tert-butyldiphenylsilyl,triisopropylsilyl, tert-butyldimethylsilyl include tetrabutylammoniumfluoride, hydrochloric acid, hydrobromic acid, hydroiodic acid, andpotassium fluoride. Of these, tetrabutylammonium fluoride is preferredfor eliminating the silyl-protecting group on the phenol.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at 0 to 120° C. for 30minutes to 1 day, more preferably 10 to 25° C. within 2 hours.

[Step G] Preparation of Compounds of Formula (X):

Compounds of formula (X) can be prepared by reacting compounds offormula (IX) with alkyl halogen acetates in the presence of a base in asolvent.

The alkyl halogen acetates are commercially available or can besynthesized by known methods in the art. The alkyl group and halogentherein include methyl, ethyl, tert-butyl and a chlorine atom, bromineatom, and iodine atom, respectively. The most preferred one among thealkyl halogen acetates is methyl (or ethyl) chloro (or bromo)acetate.

Suitable solvents usable in this reaction include N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, and acetone,with acetone being particularly preferred.

There is no specific limitation to bases used regardless of basicity,inasmuch as the base does not affect the reaction. Suitable basesinclude sodium hydride, lithium hydride, potassium hydride, sodiumhydroxide, potassium hydroxide, lithium carbonate, sodium carbonate,sodium bicarbonate, potassium carbonate, and potassium bicarbonate. Ofthese, alkali metal hydride or alkali metal carbonate is preferred, withpotassium carbonate being particularly preferred.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −10 to 120° C. for30 minutes tol day, more preferably 0 to 25° C. within 4 hours.

[Step H] Preparation of Compounds of Formula (XI):

Compounds of formula (XI) can be prepared by subjecting hydrolysis ofthe carboxylic ester of compounds of formula (X) in the presence of awater-soluble inorganic base and alcohol solvent.

Suitable solvents usable in this reaction include methanol, ethanol, andwater miscible organic solvents.

As a base usable in this reaction, about 0.1 to 6 N aqueous solution ofalkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, orpotassium hydroxide, is used. Of these, 1 to 3 N sodium hydroxide ispreferred.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −10 to 80° C. for10 minutes to 3 hours, more preferably 0 to 25° C. for 30 minutes to 1hour.

Compounds of formula (XI) obtained as above are ligands of the humanPPAR protein, PPARδ.

EXAMPLES

The present invention will next be described in detail by way ofexamples, which should not be construed as limiting the invention.

Example 1 Preparation of methyl4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole-5-carboxylate [Step A]

4-(Trifluoromethyl)thiobenzamide (20.5 g, 0.1 mol) was dissolved intetrahydrofuran (300 ml) at room temperature, and then methyl2-chloroacetoacetate (12.2 ml, 0.1 mol) was added slowly for about 20minutes therein while stirring. After completion of addition, themixture was stirred again at room temperature for 30 minutes, and thenthe mixture was heated and refluxed at 78 to 80° C. for 12 hours. Aftercompletion of the reaction, the reaction mixture was cooled to roomtemperature. Subsequently, 50% aqueous solution of sodium hydroxide (150ml) was added and stirred for 20 minutes. The resultant organic layerwas separated by extraction with ethyl acetate, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure to therebyyield 28.8 g of the title compound (yield: 95.6%).

¹H-NMR (300 MHz, CDCl₃): 8.01 (d, 2H, J=8.4 Hz), 7.64 (d, 2H, J=8.3 Hz),3.84 (s, 3H) 2.73 (s, 3H).

Example 2 Preparation of[4-methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl)-methanol [Step B]

Methyl 4-methyl-2-[4-(trifluoromethyl)phenyl]]thiazole-5-carboxylate(20.0 g, 66.4 mmol) obtained from Example 1 was dissolved in anhydrousdichloromethane (500 ml) under nitrogen atmosphere, and the reactionmixture was cooled to −78° C. Diisobutyl aluminum hydride (DIBAL-H, 166ml, 1.0 M hexane solution, 2.5 eq.) was slowly added to the solution for30 minutes, and the mixture was reacted for another 30 minutes at thesame temperature. Subsequently, the temperature was raised to −10° C.and reacted for 30 minutes. After completion of the reaction, anexcessive diisobutyl aluminum hydride was removed by ethyl acetate. Theresultant residue was extracted by 10% sulfuric acid and ethyl acetate,followed by drying over magnesium sulfate. The resultant mixture waspurified on silica flash column, followed by evaporation under reducedpressure to thereby yield 17.5 g of the title compound (yield: 96.4%).

¹H-NMR (300 MHz, CDCl₃): 7.94 (d, 2H, J=8.1 Hz), 7.63 (d, 2H, J=8.2 Hz),4.80 (s, 2H), 2.93 (bs, 1H), 2.41 (s, 3H).

¹³C-NMR (78.5 MHz, CDCl₃): 164.6, 151.0, 137.0, 133.1, 132.0 (q), 126.8,126.3 (m), 122.5, 57.1, 15.4.

Example 3 Preparation of5-bromomethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [Step C]

[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (15.0 g,55.0 mmol) obtained from Example 2 was dissolved in anhydrousdichloromethane (300 ml), and then triphenylphosphine (TPP, 5.7 g, 60.0mmol, 1.1 eq.) and tetrabromomethane (20.0 g, 60.0 mmol, 1.1 eq.) wereadded to the mixture sequencially at room temperature. After 1 hour, thesolvent was evaporated from the reaction mixture under reduced pressure.Subsequently, the remained triphenylphosphine oxide was precipitated bya mixed solvent of hexane and ethyl acetate (v/v=5/1), followed byfiltration and evaporation under reduced pressure to thereby yield 17.2g of the title compound (yield: 93%).

¹H-NMR (300 MHz, CDCl₃): 8.00 (d, 2H, J=8.1 Hz), 7.67 (d, 2H, J=8.2 Hz),4.72 (s, 2H), 2.47 (s, 3H).

¹³C-NMR (78.5 MHz, CDCl₃): 165.0, 153.8, 136.9, 132.4, 129.7 (q), 127.0,126.3 (m), 122.5, 23.8, 15.5.

Example 4 Preparation of5-bromomethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [Step C]

[4-methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (10.0 g,36.6 mmol) obtained from Example 2 was dissolved in anhydrousdichloromethane 300 ml, and then triphenylphosphine (TPP, 10.6 g, 40.3mmol, 1.1 eq.) and N-bromosuccinimide (7.17 g, 40.3 mmol, 1.1 eq.) wereadded to the mixture at room temperature. After 1 hour, the solvent wasevaporated from the reaction mixture under reduced pressure.Subsequently, the remained triphenylphosphine oxide was precipitated bya mixed solvent of hexane and ethyl acetate (v/v=5/1), followed byfiltration and evaporation under reduced pressure to thereby yield 11.1g of the title compound (yield: 90.5%).

Example 5 Preparation of5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl)thiazole [Step C]

(4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (5.0 g,18.3 mmol) obtained from Example 2 was dissolved in tetrachloromethane(300 ml), and then triphenylphosphine (TPP, 6.3 g, 23.8 mmol, 1.3 eq.)was added and the mixture was stirred under reflux for 10 hours. Aftercompletion of the reaction, the temperature of the reactor was cooled toroom temperature, and a mixed solvent of hexane and ethyl acetate(v/v=5/1) was added thereto to precipitate the remainedtriphenylphosphine oxide, followed by filtration and evaporation underreduced pressure to thereby yield 8.4 g of the title compound (yield:78.4%).

¹H-NMR (300 MHz, CDCl₃): 8.01 (d, 2H, J=8.1 Hz), 7.68 (d, 2H, J=8.2 Hz),4.79 (s, 2H), 2.51 (s, 3H).

Example 6 Preparation of5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [Step C]

[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (10.0 g,36.6 mmol) obtained from Example 2 was dissolved in anhydrousdichloromethane (250 ml) and then triphenylphosphine (TPP, 11.5 g, 44.0mmol, 1.2 eq.) and N-chlorosuccinimide (5.86 g, 44.0 mmol, 1.2 eq.) wereadded to the mixture at room temperature. After completion of thereaction, the solvent was evaporated under reduced pressure.Subsequently, the remained triphenylphosphine oxide was precipitated byadding a mixed solvent of hexane and ethyl acetate (v/v=5/1), followedby filtration and evaporation under reduced pressure to thereby yield10.5 g of the title compound (yield: 98.5%).

Example 7 Preparation of 4-iodo-2-methyl-phenoxy-tert-butyldimethylsilane [Step D]

4-Iodo-2-methylphenol (15.0 g, 64.1 mmol) was dissolved inN,N-dimethylformamide (250 ml), and imidazole (8.7 g, 128.2 mmol, 2.0eq.) added to the mixture, tert-Butyldimethyl silyl chloride (10.6 g,70.5 mmol, 1.1 eq.) was slowly added to the above mixture and stirred atroom temperature for 4 hours. After completion of the reaction, thereaction mixture was extracted with aqueous ammonium chloride solutionand ethyl acetate, and dried over magnesium sulfate. The crude productwas purified on silica flash column. The solvent was evaporated underreduced pressure to thereby yield 21.8 g of the title compound (yield:97.5%).

¹H-NMR (300 MHz, CDCl₃): 7.47 (d, 1H, J=0.6 Hz), 7.35 (dd, 1H, J=8.4,2.3 Hz), 6.54 (d, 1H, J=8.4 Hz), 2.18 (s, 3H), 1.03 (s, 9H), 0.22 (s,6H).

¹³C-NMR (78.5 MHz, CDCl₃): 154.3, 139.9, 135.9, 132.3, 121.1, 83.9,26.2, 18.7, 17.0, −3.8.

Example 8 Preparation of ethyl 4-iodo-2-methyl-phenoxyacetate [Step D]

4-Iodo-2-methylphenol (3.0 g, 12.9 mmol) was dissolved in acetone (250ml) at room temperature, and then potassium carbonate (2.67 g, 19.4mmol, 1.5 eq.) was added thereto and vigorously stirred. Ethylbromoacetate (1.56 ml, 14.1 mmol, 1.5 eq.) was quickly added to themixture, and then reacted further at room temperature for 4 hours. Aftercompletion of the reaction, the reaction mixture was extracted withaqueous ammonium chloride solution and ethyl acetate, and dried overmagnesium sulfate. The crude product was purified on silica flashcolumn. The solvent was evaporated under reduced pressure to therebyyield 4.26 g of the title compound (yield: 98.5%).

¹H-NMR (300 MHz, CDCl₃): 7.45 (d, 1H, J=0.6 Hz), 7.39 (dd, 1H, J=8.5,2.1 Hz), 6.46 (d, 1H, J=8.5 Hz), 2.18 (s, 3H), 4.59 (s, 2H), 4.24 (q,2H, J=14.3, 7.1 Hz), 2.24 (s, 3H), 1.28 (t, 3H, J=7.1 Hz).

¹³C-NMR (78.5 MHz, CDCl₃): 168.9, 156.3, 139.7, 135.7, 130.4, 113.6,84.2, 65.9, 61.1, 16.2, 14.4.

Example 9 Preparation of 4-bromo-phenoxy-tert-butyldimethyl silane [StepD]

4-Bromophenol (5.0 g, 29.0 mmol) was dissolved in N,N-dimethylformamide(150 ml), and imidazole (4.09 g, 60.0 mmol, 2.0 eq.) was added to themixture, tert-Butyldimethyl silyl chloride (4.36 g, 29.0 mmol, 1.0 eq.)was slowly added to the above mixture and stirred at room temperaturefor 4 hours. After completion of the reaction, the reaction mixture wasextracted with aqueous ammonium chloride solution and ethyl acetate, anddried over magnesium sulfate. The crude product was purified on silicaflash column. The solvent was evaporated under reduced pressure tothereby yield 8.15 g of the title compound (yield: 97.8%).

¹H-NMR (300 MHz, CDCl₃): 7.32 (d, 2H, J=8.8 Hz), 6.72 (d, 2H, J=10.0Hz), 0.98 (s, 9H), 0.18 (s, 6H).

¹³C-NMR (78.5 MHz, CDCl₃): 155.3, 132.7, 122.3, 114.0, 26.0, 18.6, −4.1.

Example 10 Preparation of5-[4-(tert-butyldimethylsilanyloxy)-3-methyl-phenylsulfanyl-methyl]-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole[Step E]

4-Iodo-2-methyl-phenoxy-tert-butyldimethyl silane (5.0 g, 14.4 mmol)obtained from Example 7 was dissolved in anhydrous tetrahydrofuran (200ml) under nitrogen atmosphere and cooled to −78° C. tert-Butyllithium(8.47 ml, 1.7 M hexane solution, 1.0 eq.) was slowly added thereto for 1minute. The mixture was stirred for 10 minutes, and sulfur powder (460mg, 14.4 mmol, 1.0 eq.) was poured into the mixture at once at the sametemperature. The mixture was stirred for 10 minutes to dissolve the saidsulfur completely, and5-bromomethyl-4-methyl-2-[(4-trifluoro-methyl)phenyl]thiazole (4.84 g,14.4 mmol, 1.0 eq.) obtained from Example 4 was added at once. Thereaction temperature was raised to room temperature slowly for about 1hour to react, followed by terminating the reaction by aqueous ammoniumchloride solution. The reaction mixture was extracted with ethyl acetateand brine. Subsequently, the organic layer was dried over magnesiumsulfate and the solvent was evaporated by under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1) to thereby yield 5.11 g of the title compound (yield:69%).

¹H-NMR (300 MHz, CDCl₃): 7.97 (d, 2H, J=8.0 Hz), 7.65 (d, 2H, J=8.2 Hz),7.17 (4, 1H, J=1.8 Hz), 7.07 (dd, 1H, J=8.2, 2.3 Hz), 6.67 (d, 1H, J=8.3Hz), 4.10 (s, 2H), 2.20 (s, 3H), 2.15 (s, 3H), 1.00 (s, 9H), 0.20 (s,6H).

¹³C-NMR (78.5 MHz, CDCl₃): 163.4, 154.9, 151.8, 136.8, 132.6, 130.4,129.6 (q), 126.8, 126.2 (m), 125.2, 119.6, 33.0, 26.1, 18.7, 17.1, 15.2,−3.9.

Example 11 Preparation of5-[4-(tert-butyldimethylsilanyloxy)-3-methyl-phenylsulfanyl-methyl]-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole[Step E]

4-Iodo-2-methyl-phenoxy-tert-butyldimethyl silane (5.0 g, 14.4 mmol)obtained from Example 7 was dissolved, while stirring, in anhydroustetrahydrofuran (150 mW) and diethyl ether 150 ml) under nitrogenatmosphere, and was cooled to −78° C. n-Butyl lithium (9.0 ml, 1.6 Mhexane solution, 1.0 eq.) was added thereto for 1 minute. The mixturewas stirred for 10 minutes and sulfur powder (460 mg, 14.4 mmol, 1.0eq.) was poured into the mixture at once at the same temperature. Themixture was stirred for 10 minutes to dissolve the said sulfurcompletely and5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole (4.14 g,14.4 mmol, 1.0 eq.) obtained from Example 5 was added at once. Thereaction temperature was raised to room temperature slowly for about 1hour to react, followed by terminating the reaction by aqueous ammoniumchloride solution. The reaction mixture was extracted with ethyl acetateand brine. Subsequently, the organic layer was dried over magnesiumsulfate and the solvent was evaporated by under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1) to thereby yield 5.51 g of the title compound (yield:78.1%).

Example 12 Preparation of5-[4-(tert-butyldimethylsilanyloxy)-phenylsulfanylmethyl]-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole[Step E]

4-Bromo-phenoxy-tert-butyldimethyl silane (5.0 g, 17.4 mmol) obtainedfrom Example 9 was dissolved in anhydrous tetrahydrofuran (300 ml) undernitrogen atmosphere and cooled to −78° C. n-Butyl lithium (10.9 ml, 1.6M hexane solution, 1.0 eq.) was added thereto for 1 minute. The mixturewas stirred for 10 minutes and sulfur powder (557 mg, 17.4 mmol, 1.0eq.) was poured into the mixture at once at the same temperature. Themixture was stirred for 10 minutes to dissolve the said sulfurcompletely and5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole (5.08 g,17.4 mmol, 1.0 eq.) obtained from Example 5 was added at once. Thereaction temperature was raised to room temperature slowly for about 1hour to react, followed by terminating the reaction by aqueous ammoniumchloride solution. The reaction mixture was extracted with ethyl acetateand brine. Subsequently, the organic layer was dried over magnesiumsulfate, and the solvent was evaporated by under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1) to thereby yield 7.3 g of the title compound (yield:84.6%).

¹H-NMR (300 MHz, CDCl₃): 7.97 (d, 2H, J=8.0 Hz), 7.65 (d, 2H, J=8.2 Hz),7.24 (d, 2H, J=8.7 Hz), 7.07 (d, 2H, J=10.0 Hz), 4.08 (s, 2H), 2.20 (5,3H), 2.17 (s, 3H), 0.97 (s, 9H), 0.17 (s, 6H).

Example 13 Preparation of2-methyl-4-{4-methyl-2-[(4-trifluoromethyl)phenyl]-thiazole-5-ylmethylsulfanyl}phenol [Step F]

5-[4-(tert-Butyldimethylsilanyloxy)-3-methyl-phenylsulfanylmethyl]-4methyl-2-[(4-trifluoromethyl)phenyl]thiazole(5.0 g, 9.8 mmol) obtained from Example 10 was dissolved intetrahydrofuran (250 ml). Tetrabutylammonium fluoride (TBAF, 24.5 ml, 1M tetrahydrofuran solution, 2.5 eq.) was slowly added at roomtemperature. After reaction for 30 minutes, the mixture was extractedwith aqueous ammonium chloride solution and ethyl acetate, and theorganic layer was dried over magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (hexane:ethyl acetate 5:1) to thereby yield3.67 g of the title compound (yield: 94.6%).

¹H-NMR (300 MHz, CDCl₃): 7.96 (d, 2H, J=8.2 Hz), 7.64 (d, 2H, J=8.3,Hz), 7.20 (d, 1H, J=1.8 Hz), 6.97 (dd, 1H, J=8.2, 2.2 Hz), 6.59 (d, 1H,J=8.2 Hz), 4.06 (s, 2H), 2.19 (s, 3H), 2.09 (s, 3H).

¹³C-NMR (78.5 MHz, CDCl₃): 163.9, 155.5, 151.7, 137.4, 133.5, 132.0,131.7, 131.6, 126.8, 126.3 (m), 125.8, 123.8, 115.7, 33.2, 16.2, 14.8.

Example 14 Preparation of ethyl{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylsulfanyl]phenoxy}acetate [Step G]

2-Methyl-4-{4-methyl-2-[(4-trifluoromethyl)phenyl]-thiazole-5-ylmethyl-sulfanyl}phenol (5.0 g, 12.5 mmol) obtained from Example 13 wasdissolved in anhydrous tetrahydrofuran (200 ml), and sodium hydride (378mg, 15.6 mmol, 1.25 eq.) was added at −10° C. Ethyl bromoacetate (2.1ml, 19.0 mmol, 1.5 eq.) was added for 2 hours while stirring vigorously.After completion of reaction, the mixture was extracted with brine andethyl acetate, and the organic layer was dried over magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified on silica flash column to thereby yield 4.6 g of the titlecompound (yield: 76.8%).

¹H-NMR (300 MHz, CDCl₃): 7.97 (d, 2H, J=8.1 Hz), 7.66 (d, 2H, J=8.3 Hz),7.21 (d, 1H, J=1.7 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.60 (d, 1H, J=8.4Hz), 4.62 (s, 2H), 4.24 (q, 2H, J=14.3, 7.1 Hz), 2.24 (s, 3H), 2.21 (s,3H), 1.28 (t, 3H, J=7.1 Hz).

¹³C-NMR (78.5 MHz, CDCl₃): 169.1, 156.8, 151.8, 136.5, 132.5, 131.1,128.8, 126.8, 126.2 (m), 125.7, 112.0, 66.0, 61.8, 32.9, 16.5, 15.2,14.5.

Example 15 Preparation of ethyl{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylsulfanyl]phenoxy}acetate [Step G]

2-Methyl-4-{4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole-5-ylmethyl-sulfanyl}phenol (10.0 g, 25.3 mmol) obtained from Example 13 wasdissolved in acetone (350 ml), and potassium carbonate (8.0 g, 58.2mmol, 2.3 eq.) was added at room temperature. Ethyl bromoacetate (4.2ml, 38.0 mmol, 1.5 eq.) was added for 4 hours while stirring vigorously.After completion of reaction, the mixture was extracted with brine andethyl acetate, and the organic layer was dried over magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified on silica flash column to thereby yield 11.8 g of the titlecompound (yield: 98.5%).

Example 16 Preparation of2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-yl}methyl)sulfanyl]phenoxy}aceticacid [Step H]

Ethyl {2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-ylsulfanyl]phenoxy}acetate (5.0 g, 10.4 mmol) obtained from Example 15 wasdissolved thoroughly in ethanol (300 ml), and 3 N sodium hydroxidesolution (35 m) was added. After stirring at room temperature for 30minutes to complete the reaction, the mixture was adjusted to pH 2.0with 1 N HCl. The mixture (ca. 80% of ethanol) was evaporated underreduced pressure, and the mixture was extracted with brine and ethylacetate. The solvent was evaporated under reduced pressure. The residuewas dissolved in methanol again and purified by LH-20 columnchromatography to thereby yield 4.71 g of the title compound (yield:98.8%).

¹H-NMR (600 MHz, CD₃OD): 7.99 (d, 2H, J=8.1 Hz), 7.72 (d, 2H, J=8.3 Hz),7.17 (s, 1H), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 6.72 (d, 1H, J=8.4 Hz), 4.65(s, 2H), 4.16 (s, 2H), 2.18 (s, 3H), 2.11 (s, 3H).

¹³C-NMR (150.9 MHz, CD₃OD): 172.7, 164.8, 158.2, 152.6, 138.2, 137.5,133.8, 133.3, 132.5 (q), 129.4, 127.8, 127.2 (m), 126.2, 112.9, 66.3,32.9, 16.4, 14.8.

INDUSTRIAL APPLICABILITY

As described above, compounds of formula (XI) can be prepared in a highyield easily, according to the present invention.

1. A process for preparing compounds of formula (XI) which comprises byreacting metal thiolate intermediate compounds of formula (VII),prepared from compounds of formula (VI), with compounds of formula (IV),to form compounds of formula (VIII), eliminating the protecting group ofthe resulted compounds of formula (VIII) to obtain compounds of formula(IX), reacting it with alkyl halogenated acetate to give compounds offormula (X), and hydrolying compounds of formula (X)

wherein R₁ represents hydrogen atom, CF₃, or halogen atom, n is aninteger of 0 to 5, R₂ represents a hydrogen atom, fluorine atom,chlorine atom. —(C₁-C₄) alkyl, —O(C₁-C₄)alkyl, —S(C₁-C₄) alkyl, or—N(C₁-C₄ alkyl)₂ group, R₃ represents protecting group having atetrahydropyranyl, —(C₁-C₄) alkyl, allyl, or silyl group, R₄ representsa —(C₄) alkyl group, X₁ represents a halogen atom, X₂ represents ahalogen atom, or leaving group easily displaced by nucleophiles, and Mrepresents a lithium ion or magnesium halide (Cl, Br, or I). 2.Compounds of formula (VI) for preparing2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-,3-thiazole-5-yl}methyl)-sulfanyl]-phenoxy}aceticacid among compounds of formula (XI) described in the claim
 1. 3.Compounds of formula (VII) for preparing2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl}-1,3-thiazole-5-yl}methyl)-sulfanyl]-phenoxy}aceticacid among compounds of formula (XI) described in the claim
 1. 4.Compounds of formula (VIII) for preparing2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-yl}methyl)sulfanyl]-phenoxy}aceticacid among compounds of formula (XI) described in the claim
 1. 5.Compounds of formula (IX) for preparing2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl}-1,3-thiazole-5-yl}methyl)-sulfanyl]-phenoxy}aceticacid among compounds of formula (XI) described in the claim
 1. 6. Aprocess for preparing compounds of formula (XI) which comprisespreparing metal thiolate intermediate compounds of formula (VII) fromcompounds of formula (VI), reacting compounds of formula (VII) withcompounds of formula (IV) to form compounds of formula (VIII),eliminating the protecting group of the compounds of formula (VIII) toobtain compounds of formula (IX), reacting the compounds of formula (IX)with alkyl halogenated acetate to produce compounds of formula (X), andhydrolyzing compounds of formula (X) to produce compounds of formula(XI)

wherein R₁ represents hydrogen atom, CF₃, or halogen atom, n is aninteger of 0 to 5, R₂ represents a hydrogen atom, fluorine atom,chlorine atom. —(C₁-C₄) alkyl, —O(C₁-C₄)alkyl, —S(C₁-C₄) alkyl, or—N(C₁-C₄ alkyl)₂ group, R₃ represents protecting group having atetrahydropyranyl, —(C₁-C₄) alkyl, allyl, or silyl group R₄ represents a—(C₄) alkyl group, X₁ represents a halogen atom, X₂ represents a halogenatom, or leaving group which can be displaced by nucleophiles, and Mrepresents a lithium ion or magnesium chloride, magnesium bromide ormagnesium iodide.
 7. Compounds of formula (VI) for use in the process ofclaim 6

wherein R₂ represents a hydrogen atom, fluorine atom, chlorine atom.—(C₁-C₄) alkyl, —O(C₁-C₄)alkyl, —S(C₁-C₄) alkyl, or —N(C₁-C₄ alkyl)₂group, R₃ represents protecting group having a tetrahydropyranyl,—(C₁-C₄) alkyl, allyl, or silyl group, and X₁ represents a halogen atom.8. Compounds of formula (VII) for use in the process of claim 6

wherein R₂ represents a hydrogen atom, fluorine atom, chlorine atom.—(C₁-C₄) alkyl, —O(C₁-C₄)alkyl, —S(C₁-C₄) alkyl, or —N(C₁-C₄ alkyl)₂group, R₃ represents protecting group having a tetrahydropyranyl,—(C₁-C₄) alkyl, allyl, or silyl group, M represents a lithium ion ormagnesium chloride, magnesium bromide, or magnesium iodide.
 9. Compoundsof formula (VIII) for use in the process of claim 6

wherein R₁ represents hydrogen atom, CF₃, or halogen atom, n is aninteger of 0 to 5, R₂ represents a hydrogen atom, fluorine atom,chlorine atom. —(C I—C₄) alkyl, —O(C₁-C₄)alkyl, —S(C₁-C₄) alkyl, or—N(C₁-C₄ alkyl)₂ group, R₃ represents protecting group having atetrahydropyranyl, —(C₁-C₄) alkyl, allyl, or silyl group.
 10. Compoundsof formula (IX) for use in the process of claim 6

wherein R₁ represents hydrogen atom, CF₃, or halogen atom, n is aninteger of 0 to 5, R₂ represents a hydrogen atom, fluorine atom,chlorine atom. —(C₁-C₄) alkyl, —O(C₁-C₄)alkyl, —S(C₁-C₄) alkyl, or—N(C₁-C₄ alkyl)₂ group.